{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T05:19:00Z","timestamp":1740028740042,"version":"3.37.3"},"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/L015358\/1"],"award-info":[{"award-number":["EP\/L015358\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["215888\/Z\/19\/Z"],"award-info":[{"award-number":["215888\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012295","name":"NIHR Newcastle Biomedical Research Centre","doi-asserted-by":"publisher","award":["203105\/A\/16\/Z"],"award-info":[{"award-number":["203105\/A\/16\/Z"]}],"id":[{"id":"10.13039\/501100012295","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Mitochondria are organelles in most human cells which release the energy required for cells to function. Oxidative phosphorylation (OXPHOS) is a key biochemical process within mitochondria required for energy production and requires a range of proteins and protein complexes. Mitochondria contain multiple copies of their own genome (mtDNA), which codes for some of the proteins and ribonucleic acids required for mitochondrial function and assembly. Pathology arises from genetic defects in mtDNA and can reduce cellular abundance of OXPHOS proteins, affecting mitochondrial function. Due to the continuous turn-over of mtDNA, pathology is random and neighbouring cells can possess different OXPHOS protein abundance. Estimating the proportion of cells where OXPHOS protein abundance is too low to maintain normal function is critical to understanding disease severity and predicting disease progression. Currently, one method to classify single cells as being OXPHOS deficient is prevalent in the literature. The method compares a patient\u2019s OXPHOS protein abundance to that of a small number of healthy control subjects. If the patient\u2019s cell displays an abundance which differs from the abundance of the controls then it is deemed deficient. However, due to the natural variation between subjects and the low number of control subjects typically available, this method is inflexible and often results in a large proportion of patient cells being misclassified. These misclassifications have significant consequences for the clinical interpretation of these data. We propose a single-cell classification method using a Bayesian hierarchical mixture model, which allows for inter-subject OXPHOS protein abundance variation. The model accurately classifies an example dataset of OXPHOS protein abundances in skeletal muscle fibres (myofibres). When comparing the proposed and existing model classifications to manual classifications performed by experts, the proposed model results in estimates of the proportion of deficient myofibres that are consistent with expert manual classifications.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012770","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T18:35:46Z","timestamp":1739990146000},"page":"e1012770","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bayesian classification of OXPHOS deficient skeletal myofibres"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4149-1790","authenticated-orcid":true,"given":"Jordan","family":"Childs","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-5363","authenticated-orcid":true,"given":"Tiago Bernardino","family":"Gomes","sequence":"additional","affiliation":[]},{"given":"Amy E","family":"Vincent","sequence":"additional","affiliation":[]},{"given":"Andrew","family":"Golightly","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4186-8506","authenticated-orcid":true,"given":"Conor","family":"Lawless","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"issue":"5806","key":"pcbi.1012770.ref001","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/290457a0","article-title":"Sequence and organization of the human mitochondrial genome","volume":"290","author":"S Anderson","year":"1981","journal-title":"Nature"},{"issue":"2","key":"pcbi.1012770.ref002","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.fertnstert.2018.11.021","article-title":"Mitochondrial DNA copy number as a predictor of embryo viability","volume":"111","author":"GN Cecchino","year":"2019","journal-title":"Fertil Steril"},{"issue":"4","key":"pcbi.1012770.ref003","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1086\/302311","article-title":"Relaxed replication of mtDNA: A model with implications for the expression of disease","volume":"64","author":"PF Chinnery","year":"1999","journal-title":"Am J Hum Genet"},{"issue":"9","key":"pcbi.1012770.ref004","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrg3966","article-title":"The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease","volume":"16","author":"JB Stewart","year":"2015","journal-title":"Nat Rev Genet"},{"issue":"3","key":"pcbi.1012770.ref005","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1086\/318801","article-title":"Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age","volume":"68","author":"JL Elson","year":"2001","journal-title":"Am J Hum Genet"},{"issue":"5","key":"pcbi.1012770.ref006","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nrg1606","article-title":"Mitochondrial DNA mutations in human disease","volume":"6","author":"RW Taylor","year":"2005","journal-title":"Nat Rev Genet"},{"issue":"2","key":"pcbi.1012770.ref007","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1002\/path.4809","article-title":"The genetics and pathology of mitochondrial disease","volume":"241","author":"CL Alston","year":"2017","journal-title":"J Pathol"},{"issue":"11","key":"pcbi.1012770.ref008","doi-asserted-by":"crossref","first-page":"5313","DOI":"10.1093\/nar\/gkw382","article-title":"Complex mitochondrial DNA rearrangements in individual cells from patients with sporadic inclusion body myositis","volume":"44","author":"KA Rygiel","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"14","key":"pcbi.1012770.ref009","doi-asserted-by":"crossref","first-page":"7430","DOI":"10.1093\/nar\/gkz472","article-title":"Understanding mitochondrial DNA maintenance disorders at the single muscle fibre level","volume":"47","author":"D Lehmann","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1012770.ref010"},{"issue":"1","key":"pcbi.1012770.ref011","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1128\/br.40.1.168-189.1976","article-title":"Uniform nomenclature for bacterial plasmids: a proposal","volume":"40","author":"RP Novick","year":"1976","journal-title":"Bacteriol Rev"},{"issue":"8","key":"pcbi.1012770.ref012","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.nmd.2012.04.003","article-title":"Cytochrome c oxidase-intermediate fibres: importance in understanding the pathogenesis and treatment of mitochondrial myopathy","volume":"22","author":"JL Murphy","year":"2012","journal-title":"Neuromuscul Disord"},{"issue":"7","key":"pcbi.1012770.ref013","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1007\/s40520-020-01698-7","article-title":"Mitochondrial DNA deletion mutations increase exponentially with age in human skeletal muscle","volume":"33","author":"A Herbst","year":"2021","journal-title":"Aging Clin Exp Res"},{"issue":"1","key":"pcbi.1012770.ref014","doi-asserted-by":"crossref","first-page":"15037","DOI":"10.1038\/srep15037","article-title":"A novel immunofluorescent assay to investigate oxidative phosphorylation deficiency in mitochondrial myopathy: understanding mechanisms and improving diagnosis","volume":"5","author":"MC Rocha","year":"2015","journal-title":"Sci Rep"},{"issue":"1","key":"pcbi.1012770.ref015","doi-asserted-by":"crossref","first-page":"15336","DOI":"10.1038\/s41598-020-70885-3","article-title":"Decoding mitochondrial heterogeneity in single muscle fibres by imaging mass cytometry","volume":"10","author":"C Warren","year":"2020","journal-title":"Sci Rep"},{"issue":"4","key":"pcbi.1012770.ref016","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s10545-017-0027-5","article-title":"MtDNA-maintenance defects: syndromes and genes","volume":"40","author":"C Viscomi","year":"2017","journal-title":"J Inherit Metab Dis"},{"issue":"2","key":"pcbi.1012770.ref017","first-page":"2045894018768290","article-title":"Skeletal muscle mitochondrial oxidative phosphorylation function in idiopathic pulmonary arterial hypertension: in vivo and in vitro study","volume":"8","author":"S Sithamparanathan","year":"2018","journal-title":"Pulmon Circulat"},{"key":"pcbi.1012770.ref018"},{"key":"pcbi.1012770.ref019"},{"issue":"11","key":"pcbi.1012770.ref020","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.nmd.2021.05.014","article-title":"A novel MT-CO2 variant causing cerebellar ataxia and neuropathy: the role of muscle biopsy in diagnosis and defining pathogenicity","volume":"31","author":"K Baty","year":"2021","journal-title":"Neuromuscul Disord"},{"issue":"5","key":"pcbi.1012770.ref021","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/j.1467-9876.2012.01045.x","article-title":"The effect of late onset, short-term caloric restriction on the core temperature and physical activity in mice","volume":"61","author":"A Golightly","year":"2012","journal-title":"J Roy Statist Soc Ser C: Appl Statist"},{"issue":"2","key":"pcbi.1012770.ref022","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/bib\/bbm007","article-title":"Bayesian methods in bioinformatics and computational systems biology","volume":"8","author":"DJ Wilkinson","year":"2007","journal-title":"Brief Bioinform"},{"issue":"2","key":"pcbi.1012770.ref023","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nrg2509","article-title":"Stochastic modelling for quantitative description of heterogeneous biological systems","volume":"10","author":"DJ Wilkinson","year":"2009","journal-title":"Nat Rev Genet"},{"issue":"1","key":"pcbi.1012770.ref024","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s12551-019-00499-1","article-title":"Bayesian statistical learning for big data biology","volume":"11","author":"C Yau","year":"2019","journal-title":"Biophys Rev"},{"key":"pcbi.1012770.ref025","article-title":"UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples","author":"AX Xie","year":"2024"},{"key":"pcbi.1012770.ref026","doi-asserted-by":"crossref","DOI":"10.1101\/2024.04.23.24306030","article-title":"A generative model for evaluating missing data methods in large epidemiological cohorts","author":"L Radosavljevic","year":"2024"},{"issue":"5","key":"pcbi.1012770.ref027","doi-asserted-by":"crossref","first-page":"167131","DOI":"10.1016\/j.bbadis.2024.167131","article-title":"A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders","author":"AE Vincent","year":"2024","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"1","key":"pcbi.1012770.ref028","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/ana.25127","article-title":"Pathological mechanisms underlying single large-scale mitochondrial DNA deletions","volume":"83","author":"MC Rocha","year":"2018","journal-title":"Ann Neurol"},{"issue":"1","key":"pcbi.1012770.ref029","doi-asserted-by":"crossref","first-page":"15676","DOI":"10.1038\/s41598-017-14623-2","article-title":"Using a quantitative quadruple immunofluorescent assay to diagnose isolated mitochondrial Complex I deficiency","volume":"7","author":"ST Ahmed","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"pcbi.1012770.ref030","doi-asserted-by":"crossref","DOI":"10.1214\/088342305000000016","article-title":"Markov chain Monte Carlo methods and the label switching problem in Bayesian mixture modeling","volume":"20","author":"A Jasra","year":"2005","journal-title":"Statist Sci"},{"key":"pcbi.1012770.ref031"},{"key":"pcbi.1012770.ref032","article-title":"RStan: the R interface to Stan","author":"Team Stan Development","year":"2020"},{"key":"pcbi.1012770.ref033","article-title":"JAGS: a program for analysis of Bayesian graphical models using Gibbs sampling. In: 3rd International Workshop on Distributed Statistical Computing (DSC 2003); Vienna","author":"M Plummer","year":"2003"},{"key":"pcbi.1012770.ref034","article-title":"HDInterval","author":"J Ngumbang","year":"2022"},{"issue":"2","key":"pcbi.1012770.ref035","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/biomet\/asz002","article-title":"Multivariate output analysis for Markov chain Monte Carlo","volume":"106","author":"D Vats","year":"2019","journal-title":"Biometrika"},{"issue":"2","key":"pcbi.1012770.ref036","doi-asserted-by":"crossref","DOI":"10.1214\/20-BA1221","article-title":"Rank-normalization, folding, and localization: an improved Ro for assessing convergence of MCMC (with discussion)","volume":"16","author":"A Vehtari","year":"2021","journal-title":"Bayesian Anal"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012770","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T18:35:58Z","timestamp":1739990158000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012770"}},"subtitle":[],"editor":[{"given":"Yang","family":"Lu","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,2,19]]},"references-count":36,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012770","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,19]]}}}